Astrocyte morphology: Diversity, plasticity, and role in neurological diseases

Abstract

Astrocytes are the most abundant glial cells in the central nervous system (CNS) and participate in synaptic, circuit, and behavioral functions. The well-developed protoplasmic astrocytes contain numerous processes forming well-delineated bushy territories that overlap by as little as 5% at their boundaries. This highly complex morphology, with up to approximately 80% of the cell's membrane constituted by fine processes with dimensions on the tens of nanometer scale and high surface area to volume ratios, comes in contact with synapses, blood vessels, and other glial cells. Recent progress is challenging the conventional view that astrocytes are morphologically homogeneous throughout the brain; instead, they display circuit- and region-specific morphological diversity that may contribute to the heterogeneous astrocyte-neuron spatiotemporal interplay in different brain areas. Further, the fine structure of astrocytes is found to be highly plastic and activity-dependent. We are beginning to understand how astrocyte structural plasticity contributes to brain functions. The change/loss of astrocyte morphology, traditionally known as a hallmark for reactive astrogliosis, is a common pathological feature in many neurological disorders. However, recent data suggest the fine structural deficits preceding reactive astrogliosis may drive disease progression. This review summarizes recent advances in astrocyte morphological diversity, plasticity, and disease-related deficits.

Keywords: astrocyte; diversity; morphology; plasticity; tripartite synapse.

Figure 1

Protoplasmic astrocyte has very complex morphology with PAPs ensheathing the synapse. A, Representative confocal image of a protoplasmic astrocyte in the somatosensory cortex of adult mouse. B, Representative 3D reconstruction of astrocytic peripheral fine processes within a given ROI (5 μm × 5 μm × 5 μm). C, Cartoon of tripartite synapse, where PAPs approach or invade the synaptic cleft. The depth of astrocyte invasion controls the functional efficacy of GLTs which consequently affects the synaptic transmission. AMPAR, α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid receptor; GLTs, glial glutamate transporters, including GLT1 and GLAST; mGluRs, metabotropic glutamate receptors; NMDAR, N‐Methyl‐D‐aspartic acid receptor; PSD, postsynaptic density. Images in A and B are provided by authors

Figure 2

PAPs plasticity regulates the astrocytic coverage of synapse and synaptic transmission. A, A synapse with limited astrocytic coverage with low glutamate uptake by GLTs but high glutamate spillover which facilitates the activation of the extrasynaptic NMDAR and mGluRs. B, Increased PAPs plasticity, induced by mGluRs‐mediated Ca²⁺ signals, enhances astrocytic coverage of synapse, with increased glutamate uptake by GLTs but decreased glutamate releasing into the extracellular space (ECS) and extrasynaptic activation. AMPAR, α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid receptor; GLTs, glial glutamate transporters, including GLT1 and GLAST; mGluRs, metabotropic glutamate receptors; NMDAR, N‐Methyl‐D‐aspartic acid receptor; PSD, postsynaptic density

Figure 3

Morphological deficits of astrocytes in the early onset of neurodegeneration. A, Cartoon presentation of an astrocyte in normal physiology condition. B, An astrocyte in the early onset of neurodegenerations with decreased fine processes and territory volume